Traumatic brain injury (TBI) is a leading cause of death and disability in children and young adults and one of the best-known environmental risk factors for chronic traumatic encephalopathy (CTE) and even Alzheimer's disease (AD). Despite the immense public health burden, targeted TBI therapies remain elusive and over 30 TBI drug trials have failed to mitigate the devastating short- and long-term sequelae of TBI. One putative target after TBI is phosphorylated tau, a defining pathological signature of CTE and AD brains, however, the role of tau-related pathology (tauopathy) in short and long term outcomes of TBI was unknown until lately. We have previously identified a unique prolyl isomerase, Pin1 that inhibits tauopathy in AD by converting the phosphorylated T231-P motif in tau (P-tau) from the toxic cis isomer to the physiologic trans. By developing the antibodies capable of distinguishing these two isomers, we find that cis P-tau is a precursor of tauopathy that instigates and propagates neurodegeneration. Notably, prominent cis P-tau is localized to axons diffusely in human CTE brains. Surprisingly, hours after single severe or repetitive mild closed head injury (ssCHI or rmCHI) in mice, neurons robustly produce cis P-tau mainly at axons, which causes and spreads ?cistauosis?, leading to axonopathy and eventually CTE-like phenotypes. Treating ssCHI or rmCHI mice with cis mAb not only blocks early cistauosis, but also prevents the later development of CTE-like neuropathology and clinically relevant brain dysfunction. Our preliminary data also demonstrate that robust cis P-tau is found at axons in several other CHI models that feature diffuse axon injury, as well as in human TBI brains, and that cis mAb blocked purified TBI cis P-tau or human TBI CSF from causing neuron death and/or brain dysfunction. Others have shown that tau knockout prevents axonopathy and memory deficits in rmCHI, Thus, therapies targeting cis P-tau are most effective in preventing axonal injury mechanisms and cis mAb therapy is a new targeted therapy for diffuse axon injury, a prominent feature and a therapeutic focus in TBI. We have assembled a multidisciplinary team to develop therapeutic cis mAb to treat or prevent short- and long-term sequelae after TBI. First, we will humanize our murine cis mAb and use the unique models and reagents that we have developed to identify humanized cis mAbs that have high affinity, specificity and potency against cis P-tau and cistauosis, and the physicochemical properties as a therapeutic antibody. Next, we will determine their PK/PD, efficacy, toxicology and safety profiles to select top 3 humanized mAb candidates, followed by their efficacy evaluation in ssCHI and rmCHI, two CHI mouse models of diffuse axon injury, and controlled cortical impact (CCI), one of severe focal injury, to assess TBI pathoanatomic subtypes best amenable to cis mAb therapy. Finally, we will evaluate efficacy of CSF cis P-tau as a theranostic biomarker. The outcome will be the development of unique targeted therapy against the early disease driver cis P-tau for mitigating the short- and long-term sequelae of TBI, with the potential to have major health impact.